TY - JOUR
T1 - MAPK pathway mutations in head and neck cancer affect immune microenvironments and ErbB3 signaling
AU - Ngan, Hoi Lam
AU - Liu, Yuchen
AU - Fong, Andrew Yuon
AU - Poon, Peony Hiu Yan
AU - Yeung, Chun Kit
AU - Chan, Sharon Suet Man
AU - Lau, Alexandria
AU - Piao, Wenying
AU - Li, Hui
AU - Tse, Jessie Sze Wing
AU - Lo, Kwok Wai
AU - Chan, Sze Man
AU - Su, Yu Xiong
AU - Chan, Jason Ying Kuen
AU - Lau, Chin Wang
AU - Mills, Gordon B.
AU - Grandis, Jennifer Rubin
AU - Lui, Vivian Wai Yan
N1 - Publisher Copyright:
© License: This article is available under a Creative Commons License (Attribution 4.0 International, as described at https://creativecommons.org/licenses/by/4.0/).
PY - 2020/5/7
Y1 - 2020/5/7
N2 - MAPK pathway mutations affect one-fifth of head and neck squamous cell carcinoma (HNSCC). Unexpectedly, MAPK pathway aberrations are associated with remarkably long patient survival, even among patients with TP53 mutations (median ~14 yr). We explored underlying outcome-favoring mechanisms with omics followed by preclinical models. Strikingly, multiple hotspot and non-hotspot MAPK mutations (A/BRAF, HRAS, MAPK1, and MAP2K1/2) all abrogated ErbB3 activation, a well-established HNSCC progression signal. Inhibitor studies functionally defined ERK activity negatively regulating phospho-ErbB3 in MAPK-mutants. Furthermore, pan-pathway immunoprofiling investigations identified MAPK-mutant tumors as the only “CD8+ T-cell-inflamed” tumors inherently bearing high-immunoreactive, constitutive cytolytic tumor microenvironments. Immunocompetent MAPK-mutant HNSCC models displayed active cell death and massive CD8+ T-cell recruitment in situ. Consistent with CD8+ T-inflamed phenotypes, MAPK-mutant HNSCC patients, independent of tumor-mutational burden, survived 3.3-4 times longer than WT patients with anti-PD1/PD-L1 immunotherapies. Similar prognosticity was noted in pan-cancers. We uncovered clinical, signaling, and immunological uniqueness of MAPK-mutant HNSCC with potential biomarker utilities predicting favorable patient survival.
AB - MAPK pathway mutations affect one-fifth of head and neck squamous cell carcinoma (HNSCC). Unexpectedly, MAPK pathway aberrations are associated with remarkably long patient survival, even among patients with TP53 mutations (median ~14 yr). We explored underlying outcome-favoring mechanisms with omics followed by preclinical models. Strikingly, multiple hotspot and non-hotspot MAPK mutations (A/BRAF, HRAS, MAPK1, and MAP2K1/2) all abrogated ErbB3 activation, a well-established HNSCC progression signal. Inhibitor studies functionally defined ERK activity negatively regulating phospho-ErbB3 in MAPK-mutants. Furthermore, pan-pathway immunoprofiling investigations identified MAPK-mutant tumors as the only “CD8+ T-cell-inflamed” tumors inherently bearing high-immunoreactive, constitutive cytolytic tumor microenvironments. Immunocompetent MAPK-mutant HNSCC models displayed active cell death and massive CD8+ T-cell recruitment in situ. Consistent with CD8+ T-inflamed phenotypes, MAPK-mutant HNSCC patients, independent of tumor-mutational burden, survived 3.3-4 times longer than WT patients with anti-PD1/PD-L1 immunotherapies. Similar prognosticity was noted in pan-cancers. We uncovered clinical, signaling, and immunological uniqueness of MAPK-mutant HNSCC with potential biomarker utilities predicting favorable patient survival.
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U2 - 10.26508/LSA.201900545
DO - 10.26508/LSA.201900545
M3 - Article
C2 - 32381551
AN - SCOPUS:85084398471
SN - 2575-1077
VL - 3
JO - Life science alliance
JF - Life science alliance
IS - 4
M1 - LSA.201900545
ER -